Background: Bipolar disorder (BD) is a serious mental illness. Several studies have shown that brain structure and function changes and the development of BD are associated with age and sex differences. Therefore, we hypothesized that the functional and structural neural circuitry of BD patients would differ according to age. The amygdala and prefrontal cortex (PFC) are play a key role in the emotional and cognitive processing of patients with BD. In this study, we used magnetic resonance imaging (MRI) to examine the structural and functional connectivity within amygdala-PFC neural circuitry in women with BD at different ages. Methods: Forty-nine female patients with BD who were aged 13–25 years and 60 age-matched healthy control (HC) individuals, as well as 43 female patients with BD who were aged 26–45 years and 60 age-matched HC individuals underwent resting-state functional MRI (rs-fMRI) and diffusion tensor imaging to examine the structural and functional connectivity within the amygdala-PFC neural circuitry. Results: We found abnormalities in the amygdala-PFC functional connectivity in patients aged 13–25 years and significantly different fractional anisotropy (FA) values in patients aged 26–45 compared with the age-matched HCs. The significance of these findings was indicated by corrected p values of less than 0.05 (uncorrected p values less than 0.001). Conclusions: The findings in this cross-sectional study suggested that abnormalities in the functional connectivity of the amygdala-PFC neural circuitry are related to the pathophysiology of BD in women aged 13–25 years, while changes in the structural integrity of this neural circuitry are associated with the pathophysiology of BD in women aged 26–45 years. Therefore, functional and structural brain alterations may occur at different ages in female patients with BD. Keywords: Bipolar disorder, Female, Age, Functional connectivity, Diffusion tensor imaging * Correspondence: email@example.com; firstname.lastname@example.org Yanqing Tang, Yinzhu Ma and Xuemei Chen contributed equally to this work. Brain Function Research Section, Department of Radiology, First Affiliated Hospital, China Medical University, 155 Nanjing North Street, Shenyang 110001, Liaoning, People’s Republic of China Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Tang et al. BMC Psychiatry (2018) 18:177 Page 2 of 8 Background In particular, the amygdala and prefrontal cortex (PFC), The human brain is a complex circuit system, and the which play a key role in emotional and cognitive process- development of the brain involves marked changes ing, have been strongly implicated in BD [18–20]. Previ- during aging. Comparisons of the brain weights of ous functional MRI analyses have provided convergent people of different ages have suggested that consider- evidence of functional abnormalities from the amygdala to able volume changes occur during brain development. PFC in BD [21–28]. Additionally, the uncinate fasciculus A review of 56 longitudinal magnetic resonance im- (UF), which is an anterior WM structure that is critically aging (MRI) studies involving several methods has indi- important for the amygdala-ventral PFC connection , cated that the volume of the whole brain changes has also been implicated in emotional and cognitive pro- throughout life , while another review has shown cessing [29–31]. Increasing evidence implicates abnormal- that age-related changes in the white matter (WM) ities in the structural integrity of uncinate WM in BD continue throughout childhood and adolescence . [32–38]. Age has been shown to have global and large effects on A more sensitive technique to use to assess WM integ- the volumes of the cortex, WM, and subcortical struc- rity is DTI, which provides quantitative information re- tures. Furthermore, regionally selective and temporally garding water mobility through tissue. The most widely heterochronological changes in the superficial WM employed DTI index, FA, estimates the directionality and magnetization transfer ratio with age have been demon- continuity of fiber tracts. Various methods of DTI data strated . Similarly, functional connectivity (FC) MRI analysis have been developed based on this technique. A studies have documented obvious changes in the devel- review of diffusion imaging studies of WM integrity in pa- opment of the human brain. A review of the develop- tients with BD compared to healthy controls (HCs) has ment of human functional brain networks has shown shown that most studies have reported decreased FA using resting-state (rs)-functional MRI (rs-fMRI) that values in specific brain regions, such as the UF . How- functional networks continue to develop from infancy ever, the functional and structural connectivity of the through adolescence . Additionally studies have sug- brains of female BD patients of different ages has not been gested that the development of the human brain fully explored. In studies of neurological disorders, FC and changes with aging [4, 5]. Several neuroimaging studies DTI methods have been combined to show abnormalities have shown that the development of the brains of pa- in both the FC and WM connections between brain re- tients with bipolar disorder (BD), which is a serious gions [40, 41]. Therefore, a combination of functional and mental illness affecting approximately 1.5–3% of the structural connectivity techniques was applied herein to general population , also changes with age [7–9]. test the study hypothesis that amygdala-PFC functional Thus, a better understanding of these age-related brain connections and the structural integrity of amygdala-PFC changes in BD is critical to distinguish BD-specific WM connections, including the UF, which provides major brain development and healthy brain development. WM connections between these structures, would differ Sex differences in brain structure and function have between patients with BD and HCs [40, 41]. In this study, been noted throughout the life span [10–13]. Female we combined DTI and rs-fMRI to examine the structural brain development may differ from male brain develop- and FC of the amygdala-PFC neural circuitry in female pa- ment because of hormonal differences. These sexual tients with BD with age ranges of 13–25 and 26–45 com- differences in brain development have also been found pared with age-matched HCs. We selected the age of 25 in patients with BD [14–16]. A voxel-based morpho- as the boundary line between the groups because the hu- metric and diffusion tensor imaging (DTI) study con- man brain is thought to be fully mature at this age . We ducted only in male bipolar patients has reported that hypothesized that the structural and FC between the the patients had greater gray matter volumes in the left amygdala and PFC would be altered in female patients thalamus and bilateral basal ganglia as well as de- with BD of different ages compared with HCs. creased fractional anisotropy (FA) values in the left posterior corona radiata . However, few studies Methods have investigated the changes that occur in the brains Participants of female bipolar patients during development and Forty-nine female patients with BD aged 13 to 25 and 60 aging. Investigations of female brain development are age-matched HC individuals were recruited for this critical in order to better distinguish sexual differences study; we also recruited 43 female patients with BD ages and better understand the underlying pathophysio- 26–45 and 60 age-matched HC participants. All partici- logical mechanisms of BD. We hypothesized that BD pants of BD were identified from the outpatient clinics patients of different ages would show differences in at the Department of Psychiatry of First Affiliated Hos- their functional and structural neural circuitry because pital of China Medical University, Shengyang, China. of the brain changes associated with age and sex. We used advertisements to recruit the HC participants Tang et al. BMC Psychiatry (2018) 18:177 Page 3 of 8 from the surrounding community. After a detailed de- first, we must convert DICOM files to NIfTI images, es- scription of the present study, all participants provided timate the brain mask, crop the images, and correct for written informed consent as approved by the ethics eddy-current effects. Next, we need to average the acqui- committee of the Institutional Review Board of China sitions and calculated DTI metrics such as fractional an- Medical University. If their age were less than 18 years isotropy and mean diffusivity for statistical analysis. old, they and their parent/legal guardian also provided Individual diffusion metric images were transformed to written informed consent. Inclusion criteria of this study Montreal Neurological Institute (MNI) space using for participants were: all BD participants met the Struc- spatial normalization with 1 mm voxels. We used the tured Clinical Interview for DSM-IV Axis I Disorders ICBM-DTI-81 WM labels for parcellation of all WM (aged > 18 years) or the Schedule for Affective Disorders into ROIs . and calculated regional diffusion metrics and Schizophrenia for School-Age Children-present and by averaging the values within each region of the WM Lifetime Version (younger than 18) criteria for Type I bi- atlas using PANDA. We selected the UF as our ROI in polar disorder, and they also did not have any other the present study. current or lifetime Axis I disorders, including alcohol and substance abuse or dependence; All HC participants Statistical analysis and their first-degree relatives did not have any history Two-sample t-tests were conducted to compare the of mental disease diagnosis measured by one of the demographic data and HAMD, YMRS, HAMA scores and above two diagnostic tools. In order to confirm and rule rs FC between the 2 groups of patients (p < 0.05) and out mental disease diagnosis, all participants were inde- group differences in the FA values in the UF (p <0.05) pendently interviewed by two trained psychiatrists. Sever- using SPSS (IBM Corporation, Armonk, NY, USA). The ities of mood symptoms were evaluated in all subjects by DTI and FC differences were separately set at corrected p the Hamilton Depression Rating Scale (HAMD), Young < 0.05 (uncorrected p < 0.001) using AlphaSim correction Manic Rating Scale (YMRS), and Hamilton Anxiety Rat- (performed using DPABI_V1.2_141101 software, http:// ing Scale (HAMA). rfmri.org/dpabi). MRI data acquisition Results MRI data was acquired at the First Affiliated Hospital of Demographic and clinical characteristics China Medical University using a GE MR Signa HDX This study recruited 49 female patients with BD who were 3.0 T MRI scanner with a standard 8-channel head coil aged 13–25 years and 60 age-matched HC individuals as as the date was obtained in our previous study . We well as 43 female patients with BD aged 26–45 years and used foam pads to minimize head motion. All partici- 60 age-matched HC individuals. The demographics and pants remained awake with their eyes closed for the clinical characteristics of the female participants are duration of the scan. The fMRI data were acquired in shown in Table 1. No significant differences were observed parallel with the anterior–posterior commissure plane in age (p =0.58, p = 0.33) between the total BD and HC using a spin echo planar sequence. We used the follow- groups aged 13–25 and 26–45 years. Compared to the ing parameters: repetition time (TR) = 2000 ms; echo HCs, the participants with BD had significantly greater time (TE) = 40 ms; matrix = 64 × 64; field of view (FOV) levels of depression, mania, and/or anxiety, which were = 24 × 24 cm ; 35 three-millimeter slices without gap; measured by HAMD, YMRS, and HAMA (p <0.001). and scan time = 6 min 40 s. FC and DTI results FC and DTI processing We found 4 PFC regions that were significantly different FC and DTI data processing followed our prior studies between HC and participants with BD aged 13–25 years [42, 43]. For the FC analysis, we performed a correl- (Table 2; Fig. 1). The rs FC of the amygdala-PFC did not ation between the amygdala as the seed region of inter- differ significantly between HCs and BD patients aged est (ROI) and all PFC voxels using REST. We defined 26–45 years. These findings corresponded to a corrected the bilateral amygdala ROI using the automated ana- p < 0.05 (uncorrected p < 0.001). tomical labeling template . In our study the PFC FA values did not differ significantly in the UF between mask included Brodmann areas 9–12, 24, 25, 32, and the HCs and BD patients aged 13–25 years (right uncin- 44–47 created using the normalized T1-weighted im- ate: t = 0.24, p = 0.77; left uncinate: t = − 0.05, p = 0.96). ages of all subjects, which were first skull-stripped However, the FA values differed significantly in the UF using BrainSuite2 (http://brainsuite.usc.edu). between HCs and BD patients aged 26–45 years. These DTI data were processed using the Pipeline for Ana- findings corresponded to a corrected p < 0.05 (uncor- lysing brain Diffusion images (PANDA) software  rected p < 0.001) (Fig. 2). Compared with HCs, the BD (version 1.2.3, http://www.nitrc.org/projects/panda/). At group aged 26–45 years had significantly decreased FA Tang et al. BMC Psychiatry (2018) 18:177 Page 4 of 8 Table 1 Demographic and clinical characteristics of the female participants Female participants aged 13 to 25 Female participants aged 26 to 45 2 2 Variable BD (n = 49) HC (n = 60) T/χ p BD (n = 43) HC (n = 60) T/χ p Age (years) 19.90(3.32) 20.27(3.51) −0.56 0.58 32.51(5.31) 33.75(6.87) −.99 0.33 Race 2.24 0.14 0.77 0.38 Han 34(69.39) 49(81.67) 38(88.37) 56(93.33) Minority 15(30.61) 11(18.33) 5(11.63) 4(6.67) Education (years) 12.37(2.74) 13.59(2.67) 0.56 0.58 14.10(3.23) 14.97(3.32) 1.29 0.20 HAMD 11.06(9.18) 1.44(1.62) 7.09 .000 12.57(11.69) 0.96(1.68) 6.39 .000 YMRS 7.48(10.34) 0.21(0.89) 4.86 .000 12.57(11.69) 0.31(0.96) 3.93 .000 HAMA 8.51(8.98) 0.91(1.56) 5.61 .000 9.24(10.51) 1.07(2.14) 4.90 .000 State Depressed 23(46.94) –– – 20(46.51) –– – Manic 14(28.57) –– – 5(11.63) –– – Stable 12(24.49) –– – 18(41.86) –– – First episode, yes 31(63.27) –– – 14(32.56) –– – Medication, yes 32(65.30) –– – 29(67.44) –– – Duration (month) 22.06(23.24) –– – 70.26(78.32) –– – Data are n (%) or mean (SD). BD bipolar disorder, HC Healthy controls, SD Standard Deviation, HAMD Hamilton Depression Rating Scale, BPRS Brief Psychiatric Rating Scale, HAMA Hamilton Anxiety Rating Scale values in the UF (right uncinate: t = 3.35, p = 0.001; left of abnormalities in the FC of the amygdala-PFC neural uncinate: t = 3.40, p = 0.001). circuit in young female patients with BD and disruptions Additional exploratory ANCOVA analyses (or in the structural integrity of uncinate WM in older female two-sample t tests) and correlation analyses were per- patients in BD. Therefore, the FC of the amygdala-PFC formed to determine the effects of states, first-episode neural circuit may be impaired in female patients with BD status, medication status, and duration on Z values in during adolescence and young adulthood, while the struc- BD patients aged 13–25 years and FA values in BD pa- tural integrity of this neural circuit may be impaired in fe- tients aged 26–45 years (see Additional file 1). The male patnts with BD during adulthood. We speculate that ANCOVA analysis showed significant differences in the these findings are significantly related to brain develop- FC of the amygdala-ventral and dorsal PFC in female pa- ment, female hormone levels, and the course of the dis- tients with BD aged 13–25 years. Post hoc analyses ease. When patients with BD are 13–25 years old, the showed increased FC in patients in the manic state disease may cause serious damage to the function of the group compared with those in the stable state group in brain and no obvious damage to the structural brain patients aged 13–25 years (t = − 0.11, p = 0.01). because the course of BD is relatively short. However, when the patients are 26–45 years, the brain is mature Discussion while the female endocrine system is stabilizing, resulting In this study, we detected abnormalities in amygdala-PFC in brain function that is relatively perfect. Thus, although FC in patients aged 13 to 25 as well as significantly differ- the damage to brain function is not obvious because of ent FA values in the UF in patients aged 26 to 45 com- the improvements in and compensation of the brain’s pared with HCs. These findings provide the first evidence functional system, the damage to brain structure becomes Table 2 Bilateral amygdala showing significant changes in functional connectivity between patients with bipolar disorder (BD) and healthy controls aged 13–25 years MNI Coordinates Cortical Regions Cluster Size X Y Z T values CL1_Ventral and dorsal prefrontal cortex 903 −51 42 −12 − 5.49 CL2_Ventral prefrontal cortex 47 33 51 −12 −4.11 CL3_Dorsal lateral prefrontal cortex 105 54 36 15 −4.39 CL4_Dorsal lateral prefrontal cortex 94 39 27 33 −5.04 CL cluster; These findings correspond to a corrected P < 0.05 Tang et al. BMC Psychiatry (2018) 18:177 Page 5 of 8 Fig. 1 Results of two-sample t-tests showing abnormalities in the resting-state functional connectivity of the amygdala-prefrontal cortex (PFC) circuit in patients with bipolar disorder (BD) compared with healthy controls aged 13–25 years. The significance of these findings corresponded to a corrected p value of < 0.05 (uncorrected p value of < 0.001) significant with longer duration of the disease. Additional adulthood. Previous studies have also reported that ad- exploratory ANCOVA analyses (or two-sample t tests) olescents and young adults with BD exhibit abnormal- and correlation analyses were performed to determine the ities in the amygdala and PFC and in amygdala-PFC effects of clinical characteristics on FC/FA in each age function [49–52]. However, sex differences were not ex- group. The results suggested that only the state affected amined in those studies. For example, in the rs, youth the FC of the amygdala-ventral and dorsal PFC cir- with BD have abnormal connections in the network be- cuitry between manic and stable groups in female pa- tween the amygdala and regions that are critical for tients with BD aged 13–25 years. This requires emotional processing and self-awareness . FC in the further research to explore the effects of state on ventral anterior cingulate and orbitofrontal cortices has disease. been shown to be decreased in an adolescent BD group The amygdale-PFC neural circuit appears to be an compared to a HC group during the processing of emo- important component of brain development during tional faces . These findings suggest that the effects adolescence [47, 48]. Our results indicated that female of the FC of prefrontal regions and the amygdala are patients with BD had abnormalities in the FC of the decreased in working memory networks in pediatric amygdala-PFC circuit during adolescence and young BD. Garrett et al.  have suggested with their fMRI Fig. 2 Results of two-sample t-tests showing abnormalities in fractional anisotropy (FA) in patients with bipolar disorder (BD) compared with healthy controls aged 26–45 years. The significance of these findings corresponded to a corrected p value of < 0.05 (uncorrected p value of < 0.001) Tang et al. BMC Psychiatry (2018) 18:177 Page 6 of 8 results that the PFC regulation of heightened amygdala change in this neural circuit may be related to the responses to emotional stimuli is deficient in pediatric pathophysiology of BD in females during adulthood. patients with BD. Additionally, abnormalities in the A number of limitations should be noted in this study. volumes of the amygdala and PFC [8, 54] have First, this is a cross-sectional, not a longitudinal, study; been shown in adolescents and young adults with BD. therefore, any conclusions must be confirmed by future Therefore, we have speculated that the changes in this research. Second, we did not detect significant main ef- neural circuit may be related to the pathophysiology of fects of mood states on FC and structural integrity. Third, BD in females during adolescence and young adult- this study lacked the socioeconomic information, which hood. Additional support for our speculation has been must be supplemented in future. Fourth, we only investi- shown in offspring (mean age = 13.8 years) of parents gated abnormalities of the functional and structural neural with BD who exhibit altered amygdala-PFC responses circuitry in females with BD, and we did not study males to facial emotion . However, our results did not show with BD. Additionally, our relatively small sample size any change in rs FC from the amygdala to the PFC in fe- may limit the generalization of our results. Future studies male patients with BD aged 26 to 45. In the adult female with a larger sample size that includes males of different patients, the function of the amygdala-PFC neural cir- ages will be important to further understand the neuro- cuitry was not altered, which was not consistent the re- pathophysiology of BD. sults of other studies of male and female subjects with BD. FC with a low frequency between the ventral PFC and Conclusion amygdala during the rs has been reported as abnormal in Our findings by a cross-sectional study have provided adults with BD . Additional studies have reported a evidence that alterations in functional and structural brain dysfunctional connection in the prefrontal-amygdala development may occur at different age stages in female circuitry in adults with BD [25, 28]. Adults with BD patients with BD. During adolescence and young adult- exhibit increased amygdala-medial PFC connectivity and hood, abnormalities were observed in the FC of the decreased connectivity between the amygdala and dorso- amygdala-PFC neural circuit, while the structural integrity lateral PFC . The studies that have included male of this neural circuit was altered during adulthood. These subjects may have contributed to the differences in the findings may be associated with the pathophysiology of findings compared with those of our study. Thus, the in- BD in females. consistent results between our study and previous studies were probably due to the inclusion of only women in our Additional file study, and it may be due to differences in sex. Future stud- Additional file 1: Relationship between FC of amydala-PFC or FA and ies are needed to further investigate this issue. clinical characteristics in the female BD group aged 13 to 25 or aged 26 Interestingly, our results indicated significant differ- to 45. (DOC 43 kb) ences in the FA values in the UF in female patients with BD aged 26–45 years, suggesting that the structural in- Abbreviations tegrity of this neural circuit is impaired in female pa- BD: Bipolar disorder; BPRS: Brief Psychiatric Rating Scale; DTI: Diffusion tensor imaging; FA: Fractional anisotropy; HAMA: Hamilton Anxiety Rating Scale; tients with BD during adulthood. This is consistent with HAMD: Hamilton Depression Rating Scale; HC: Healthy controls; the results of previous structural studies that included PFC: Prefrontal cortex; rs-fMRI: Resting-state functional magnetic resonance both adult men and women and reported significantly imaging; SCID: Structured Clinical Interview for DSM-IV Axis I Disorders; UF: Uncinate fasciculus; WM: White matter decreased FA in BD patients during adulthood compared with the control group [9, 34, 36, 37, 55]. In contrast, Acknowledgments other studies have shown that adult patients with BD ex- We would like to thank the patients and family members who contributed so much to this study and the First Affiliated Hospital of China Medical hibit significantly increased FA compared with healthy University for its active support of the project. controls in the left UF [32, 33]. The reason for this dif- ference may also be due to our study only including fe- Funding male participants and the differences in sex. This also This work was supported by grants from the National Natural Science Foundation of China (81271499 and 81571311 to Yanqing Tang, 81725005 requires future investigations. However, our results did and 81571331 to Fei Wang), Liaoning Pandeng Scholar (to Fei Wang), not indicate any changes in FA in the UF in female pa- National Keyresearch and Development Program (2016YFC0904300 to Fei tients with BD aged 13–25 years, thus suggested that BD Wang), National High Tech Development Plan (863)(2015AA020513 to Fei Wang), National Keyresearch and Development Program (2016YFC1306900 during adolescence and young adulthood in the females to Yanqing Tang). The funding body did not participate in the design of the did not damage the structure of the UF. However, this is study and collection, analysis, and interpretation of data and in writing the not consistent with the results of a previous study of manuscript. both male and female subjects that reported FA changes Availability of data and materials in the UF of adolescents with BD . Taking all of the The datasets used and/or analyzed during the current study are available results into account, we speculate that the structural from the corresponding author on reasonable request. Tang et al. BMC Psychiatry (2018) 18:177 Page 7 of 8 Authors’ contributions 14. Womer FY, Wang F, Chepenik LG, Kalmar JH, Spencer L, Edmiston E, FW and SW designed the experiment. YM, XC and XF acquired the data. XJ Pittman BP, Constable RT, Papademetris X, Blumberg HP. Sexually and YZ analyzed the data. YT, FW and SW wrote the manuscript. All the dimorphic features of vermis morphology in bipolar disorder. authors discussed the results and reviewed the manuscript. Bipolar Disord. 2009;11(7):753–8. 15. Mackay CE, Roddick E, Barrick TR, Lloyd AJ, Roberts N, Crow TJ, Young AH, Ferrier IN. Sex dependence of brain size and shape in bipolar disorder: an Ethics approval and consent to participate exploratory study. Bipolar Disord. 2010;12(3):306–11. 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Biol Psychiatry. 2012; Springer Nature remains neutral with regard to jurisdictional claims in 71(7):603–10. published maps and institutional affiliations. 19. Dell'Osso B, Cinnante C, Di Giorgio A, Cremaschi L, Palazzo MC, Cristoffanini M, Fazio L, Dobrea C, Avignone S, Triulzi F, et al. Altered prefrontal cortex Author details activity during working memory task in bipolar disorder: a functional Brain Function Research Section, Department of Radiology, First Affiliated magnetic resonance imaging study in euthymic bipolar I and II patients. J Hospital, China Medical University, 155 Nanjing North Street, Shenyang Affect Disord. 2015;184:116–22. 110001, Liaoning, People’s Republic of China. Department of Psychiatry, First 20. Blumberg HP, Leung HC, Skudlarski P, Lacadie CM, Fredericks CA, Harris Affiliated Hospital, China Medical University, 155 Nanjing North Street, BC, Charney DS, Gore JC, Krystal JH, Peterson BS. 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Published: Jun 5, 2018